EP2941433B1 - Verfahren zur herstellung von 7-substituierten 6,14-ethenomorphinanen und 7-substituierten 6,14-ethenomorphinanen - Google Patents
Verfahren zur herstellung von 7-substituierten 6,14-ethenomorphinanen und 7-substituierten 6,14-ethenomorphinanen Download PDFInfo
- Publication number
- EP2941433B1 EP2941433B1 EP13823994.2A EP13823994A EP2941433B1 EP 2941433 B1 EP2941433 B1 EP 2941433B1 EP 13823994 A EP13823994 A EP 13823994A EP 2941433 B1 EP2941433 B1 EP 2941433B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- group
- alkenyl
- heterocyclo
- cycloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 7 -substituted 6 ,14 -ethenomorphinans Chemical class 0.000 title claims description 153
- 238000004519 manufacturing process Methods 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 166
- 150000001875 compounds Chemical class 0.000 claims description 120
- 239000000203 mixture Substances 0.000 claims description 119
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 108
- 239000002253 acid Substances 0.000 claims description 95
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 92
- 125000005843 halogen group Chemical group 0.000 claims description 91
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 90
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 80
- 239000002244 precipitate Substances 0.000 claims description 80
- 238000000034 method Methods 0.000 claims description 79
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 78
- 125000001424 substituent group Chemical group 0.000 claims description 74
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 67
- 239000012452 mother liquor Substances 0.000 claims description 66
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 65
- 125000003342 alkenyl group Chemical group 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 61
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 58
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 50
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 45
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 43
- 239000002904 solvent Substances 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 125000003545 alkoxy group Chemical group 0.000 claims description 40
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 125000001188 haloalkyl group Chemical group 0.000 claims description 36
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 32
- 125000000304 alkynyl group Chemical group 0.000 claims description 29
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 29
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 16
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 13
- 229960004592 isopropanol Drugs 0.000 claims description 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 12
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 12
- 125000005518 carboxamido group Chemical group 0.000 claims description 12
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 12
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 11
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 11
- 239000012458 free base Substances 0.000 claims description 11
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 11
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 10
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000003849 aromatic solvent Substances 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical group C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 4
- HLHNOIAOWQFNGW-UHFFFAOYSA-N 3-bromo-4-hydroxybenzonitrile Chemical compound OC1=CC=C(C#N)C=C1Br HLHNOIAOWQFNGW-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 description 43
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 35
- 238000011084 recovery Methods 0.000 description 32
- 239000000243 solution Substances 0.000 description 28
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 20
- 229940125904 compound 1 Drugs 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 238000002955 isolation Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 208000002193 Pain Diseases 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- RMRJXGBAOAMLHD-CTAPUXPBSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-CTAPUXPBSA-N 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 10
- ZKLXUUYLEHCAMF-UUWFMWQGSA-N Oripavine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ZKLXUUYLEHCAMF-UUWFMWQGSA-N 0.000 description 10
- ZKLXUUYLEHCAMF-UHFFFAOYSA-N Oripavine Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(O)C5=C4C23C1O5 ZKLXUUYLEHCAMF-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 10
- 229940125898 compound 5 Drugs 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical class C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 9
- 229960001736 buprenorphine Drugs 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 229930003945 thebaine Natural products 0.000 description 8
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 6
- 239000011976 maleic acid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000006345 epimerization reaction Methods 0.000 description 5
- 239000001530 fumaric acid Substances 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 4
- 208000000094 Chronic Pain Diseases 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- CDXSJGDDABYYJV-UHFFFAOYSA-N acetic acid;ethanol Chemical compound CCO.CC(O)=O CDXSJGDDABYYJV-UHFFFAOYSA-N 0.000 description 4
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 4
- 208000005298 acute pain Diseases 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- 102000051367 mu Opioid Receptors Human genes 0.000 description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 108020001612 μ-opioid receptors Proteins 0.000 description 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 3
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- OIJXLIIMXHRJJH-KNLIIKEYSA-N Diprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)C(C)(C)O)OC)CN2CC1CC1 OIJXLIIMXHRJJH-KNLIIKEYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 159000000021 acetate salts Chemical class 0.000 description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 3
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- CAHCBJPUTCKATP-FAWZKKEFSA-N etorphine Chemical compound O([C@H]1[C@@]2(OC)C=C[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O CAHCBJPUTCKATP-FAWZKKEFSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 3
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical group C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 3
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 3
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- 108020001588 κ-opioid receptors Proteins 0.000 description 3
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- IAPQYJWHSSIDMN-UHFFFAOYSA-N 1-cycloundecyl-1,2-diazacycloundec-7-ene Chemical compound C1CCCCCC(CCCC1)N1CCCC=CCCCCN1 IAPQYJWHSSIDMN-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 208000026251 Opioid-Related disease Diseases 0.000 description 2
- 240000001090 Papaver somniferum Species 0.000 description 2
- 235000008753 Papaver somniferum Nutrition 0.000 description 2
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 108700023159 delta Opioid Receptors Proteins 0.000 description 2
- 102000048124 delta Opioid Receptors Human genes 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 229950002494 diprenorphine Drugs 0.000 description 2
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 229950004155 etorphine Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004924 2-naphthylethyl group Chemical group C1=C(C=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- YTSZWZIGGMSUPQ-LRRMBCNDSA-N CC(C[C@@](C[C@@H]1C#N)([C@@H]2N(C)CC3C2Cc2ccc4OCc5ccccc5)[C@]33c2c4O[C@H]32)[C@@]12OC Chemical compound CC(C[C@@](C[C@@H]1C#N)([C@@H]2N(C)CC3C2Cc2ccc4OCc5ccccc5)[C@]33c2c4O[C@H]32)[C@@]12OC YTSZWZIGGMSUPQ-LRRMBCNDSA-N 0.000 description 1
- YUAMOTVQCHPCBV-FUSZNBOHSA-N CC([C@H](C[C@](C(Cc1ccc2OCc3ccccc3)N(C)CC3)(C33c1c2O[C@H]31)C=C2)[C@@]12OC)=O Chemical compound CC([C@H](C[C@](C(Cc1ccc2OCc3ccccc3)N(C)CC3)(C33c1c2O[C@H]31)C=C2)[C@@]12OC)=O YUAMOTVQCHPCBV-FUSZNBOHSA-N 0.000 description 1
- FZJUZRYFACZKAE-YJPMHWTISA-N CC([C@]1([C@H](CC2[C@]34CCC(C)[C@@H]2C2)C#N)OC)[C@@]13Oc1c4c2ccc1OCc1ccccc1 Chemical compound CC([C@]1([C@H](CC2[C@]34CCC(C)[C@@H]2C2)C#N)OC)[C@@]13Oc1c4c2ccc1OCc1ccccc1 FZJUZRYFACZKAE-YJPMHWTISA-N 0.000 description 1
- FHNVNVSRUULYLZ-BWTHOKCKSA-N CN(CC(C1Cc2ccc3OCc4ccccc4)[C@]45c2c3O[C@H]42)[C@H]1[C@]5(C[C@H]1C#N)C=C[C@]21OC Chemical compound CN(CC(C1Cc2ccc3OCc4ccccc4)[C@]45c2c3O[C@H]42)[C@H]1[C@]5(C[C@H]1C#N)C=C[C@]21OC FHNVNVSRUULYLZ-BWTHOKCKSA-N 0.000 description 1
- RCWZXGVGILMKPF-ULOKJQPOSA-N C[C@H](C(C1)C(CNC)[C@@]23c4c1cc1)[C@]2(C[C@H]([C@]25OC)C(C)=O)C=C2[C@]35Oc4c1OCc1ccccc1 Chemical compound C[C@H](C(C1)C(CNC)[C@@]23c4c1cc1)[C@]2(C[C@H]([C@]25OC)C(C)=O)C=C2[C@]35Oc4c1OCc1ccccc1 RCWZXGVGILMKPF-ULOKJQPOSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 235000018159 Papaver bracteatum Nutrition 0.000 description 1
- 241001596485 Papaver bracteatum Species 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- QPMSXSBEVQLBIL-CZRHPSIPSA-N ac1mix0p Chemical compound C1=CC=C2N(C[C@H](C)CN(C)C)C3=CC(OC)=CC=C3SC2=C1.O([C@H]1[C@]2(OC)C=CC34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O QPMSXSBEVQLBIL-CZRHPSIPSA-N 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 1
- UAIXRPCCYXNJMQ-RZIPZOSSSA-N buprenorphine hydrochlorie Chemical compound [Cl-].C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)C[NH+]2CC1CC1 UAIXRPCCYXNJMQ-RZIPZOSSSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004090 cyclononenyl group Chemical group C1(=CCCCCCCC1)* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- BRTSNYPDACNMIP-FAWZKKEFSA-N dihydroetorphine Chemical compound O([C@H]1[C@@]2(OC)CC[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O BRTSNYPDACNMIP-FAWZKKEFSA-N 0.000 description 1
- 125000004990 dihydroxyalkyl group Chemical group 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001793 isothiazol-3-yl group Chemical group [H]C1=C([H])C(*)=NS1 0.000 description 1
- 125000004500 isothiazol-4-yl group Chemical group S1N=CC(=C1)* 0.000 description 1
- 125000004501 isothiazol-5-yl group Chemical group S1N=CC=C1* 0.000 description 1
- 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 description 1
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 description 1
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 125000005358 mercaptoalkyl group Chemical group 0.000 description 1
- ZUVAACFIEPYYOP-UHFFFAOYSA-N methoxycyclopropane Chemical compound COC1CC1 ZUVAACFIEPYYOP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000005040 opiate dependence Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 1
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- UCUUFSAXZMGPGH-UHFFFAOYSA-N penta-1,4-dien-3-one Chemical compound C=CC(=O)C=C UCUUFSAXZMGPGH-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940053209 suboxone Drugs 0.000 description 1
- 229940095172 subutex Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/09—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
- C07D489/10—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
- C07D489/12—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14 the bridge containing only two carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Definitions
- This application is in the field of medicinal chemistry.
- the application relates to a novel process for preparing 7 ⁇ -substituted 6 ⁇ ,14 ⁇ -ethenomorphinans and 7 ⁇ -substituted 6 ⁇ ,14 ⁇ -ethanomorphinans, and the pharmaceutically acceptable salts thereof.
- the application relates to the selective precipitation of 7 ⁇ -substituted 6 ⁇ , 14 ⁇ -ethenomorphinans or- 7 ⁇ -substituted 6 ⁇ ,14 ⁇ -ethanomorphinans from a mixture containing corresponding 7 ⁇ -epimers by treating with an acid.
- 6 ⁇ ,14 ⁇ -Ethenomorphinans and 6 ⁇ ,14 ⁇ -ethanomorphinans are semi-synthetic oripavine or thebaine derivatives.
- the central structural element of this class of molecules is a morphinan ring system with an etheno or ethano bridge between the C-6 and C-14 carbons of the morphinan scaffold. Based on the nature of the carbon-carbon-bond between C-18 and C-19, these compounds are classified as 6 ⁇ ,14 ⁇ -ethenomorphinans (carbon-carbon-double bond) or 6 ⁇ ,14 ⁇ -ethanomorphinans (saturated carbon-carbon bond).
- the morphinan scaffold has the following structure:
- Buprenorphine Temgesic®, Subutex®, Suboxone®
- Diprenorphine Revivon®
- Etorphine Immobilon®
- Buprenorphine (2 S )-2-[17-cyclopropylmethyl-4,5 ⁇ -epoxy-3-hydroxy-6-methoxy-6 ⁇ ,14 ⁇ -ethanomorphinan-7 ⁇ -yl]-3,3-dimethylbutan-2-ol, a semi-synthetic opioid having the structure: is used to treat opioid addiction, to control moderate acute pain in non-opioid tolerant individuals, and to control moderate chronic pain.
- Buprenorphine can be derived from either oripavine or thebaine. K.W. Bentley discovered buprenorphine using thebaine as the initial backbone structure. Thebaine is one of the main alkaloids in the Egyptian poppy ( Papaver bracteatum ). Thebaine can also be isolated from Papaver somniferum which is also a source for oripavine ( U.S. Pat. No. 6,723,894 ).
- Buprenorphine has an extremely high binding affinity at the ⁇ - and ⁇ -opioid receptors. It has partial agonist activity at the ⁇ -opioid receptor, partial or full agonist activity at the ORL-1/nociception and ⁇ -opioid receptors, and competitive antagonist activity at the ⁇ -opioid receptor. Buprenorphine exhibits an analgesic effect approximately 25 to 40 times more potent than morphine (by weight of equivalent low doses). Buprenorphine is marketed as oral formulations (tablets, sublingual tablets, and sublingual films), parenteral preparations, and transdermal patches.
- Figure 1 can be single bond or a double bond.
- Biochemical characterization of ⁇ -etorphine and ⁇ -dihydroetorphine derivatives indicate that the 7 ⁇ -substituted derivatives have a comparable high affinity for opioid binding sites as their corresponding 7 ⁇ -substituted analogs ( Biyashev et al., European Journal of Pharmacology 442:23-27 (2002 )).
- US 3,562,279 discloses compounds of the class of substituted 7,8-dihydro-6-methoxy-6,14-endo(etheno or ethano)morphide-7-ketones and N-cycloalkylmethyl-7,8-dihydro-6-methoxy-6,14-endo (etheno or ethano)nor-codide-7-ketones which are described to possess analgesic activity.
- 7 ⁇ -Substituted 6 ⁇ ,14 ⁇ -ethenomorphinans and 7 ⁇ -substituted 6 ⁇ ,14 ⁇ -ethanomorphinans may be attractive chemotypes with potentially new pharmacological properties.
- the isolation processes of 7 ⁇ -6 ⁇ ,14 ⁇ -ethenomorphinans and 7 ⁇ -6 ⁇ ,14 ⁇ -ethenomorphinans described in the art require multiple process steps and afford the product only in a very low yield.
- the present disclosure provides a process for increasing the proportion of the 7 ⁇ -epimer in an 7 ⁇ /7 ⁇ -epimer mixture of a 7-substituted 6 ⁇ ,14 ⁇ -ethenomorphinan or a 7-substituted 6 ⁇ ,14 ⁇ -ethanomorphinan.
- Said process comprises contacting a solution of the 7 ⁇ /7 ⁇ -epimer mixture with an acid to provide a precipitate, and isolating the precipitate to provide an isolated precipitate and a mother liquor.
- the acid is an achiral acid. In another embodiment, the acid is a chiral acid.
- the present disclosure provides a process for increasing the proportion of the 7 ⁇ -epimer in an 7 ⁇ /7 ⁇ -epimer mixture of compounds represented by Formula I , below.
- the 7 ⁇ -epimer is of Formula V b , below.
- the present disclosure provides a process for purifying the 7 ⁇ -epimer from a 7 ⁇ /7 ⁇ -epimer mixture of a 7-substituted 6 ⁇ ,14 ⁇ -ethenomorphinan or a 7-substituted 6 ⁇ ,14 ⁇ -ethanomorphinan.
- the process comprises contacting a solution of the 7 ⁇ /7 ⁇ -epimer mixture with an acid under conditions conducive to precipitation of the 7 ⁇ -epimer, and then isolating the precipitate.
- the isolation of the precipitate leaves behind a residual mother liquor.
- the acid is an achiral acid.
- the acid is a chiral acid.
- the present disclosure provides a process for purifying the 7 ⁇ -epimer from a 7 ⁇ /7 ⁇ -epimer mixture of compounds represented by Formula I , below.
- the 7 ⁇ -epimer is of Formula V b , below.
- the present disclosure also provides a process for preparing 7 ⁇ -substituted compounds of Formula I , and the pharmaceutically acceptable salts thereof.
- the process comprises, conducting a Diels-Alder reaction to form a 7 ⁇ /7 ⁇ -epimer mixture; forming a first precipitate of the 7 ⁇ /7 ⁇ -epimer mixture; isolating the first precipitate from the reaction mixture to obtain a first mother liquor; optionally reducing the volume of the first mother liquor, and contacting the first mother liquor with an acid to provide a second precipitate; isolating the second precipitate to obtain the 7 ⁇ -substituted compound as a salt and a second mother liquor; and optionally converting the salt into its free base.
- the second mother liquor is optionally epimerized and contacted with the acid to obtain the the 7 ⁇ -substituted compound as a salt.
- the present disclosure also provides novel isolated compounds of Formula I and salts thereof, and specifically compounds of Formula V b and salts thereof.
- the present disclosure also provides Compounds and or a salt thereof.
- the use of these compounds or a salt thereof as a medicament is provided.
- the compounds or a salt thereof are used in treatment or prevention of pain, such as acute pain, chronic pain, or surgical pain.
- the present disclosure provides use of these Compounds of the Invention or a salt thereof in the manufacture of a medicament for treating or preventing pain, such as acute pain, chronic pain, or surgical pain.
- the present disclosure further provides methods of treating or preventing pain, comprising administering to a patient in need thereof a therapeutically effective amount of a Compound of the Invention.
- the pain includes acute pain, chronic pain, and surgical pain.
- the disclosure provides a pharmaceutical composition, comprising a therapeutically effective amount of any one of the above compounds or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
- 6 ⁇ ,14 ⁇ -Ethenomorphinans are synthesized in the literature using a synthetic pathway comprising of a Diels-Alder reaction between a morphinan-6,8-diene and a dienophile as shown below in Scheme 1.
- the 6-methoxy group determines the stereo- and regioselectivity of the Diels-Alder reaction by polarizing the diene system, and the major product of the cycloaddition reaction is the 7 ⁇ -substituted 6 ⁇ ,14 ⁇ -ethenomorphinan along with a minor amount ( ⁇ 1-5%) of the 7 ⁇ -substituted isomer (except for compounds where CN is in the position for R 3 , wherein the product of the cycloaddition reaction forms an about 1:1 mixture of 7 ⁇ -and 7 ⁇ - epimers).
- the 7 ⁇ -substituted 6 ⁇ ,14 ⁇ -ethenomorphinan is a precipitate that is isolated by a simple filtration and usually obtained in high purity without the need for an additional purification process. Since the 7 ⁇ -substituted derivative is accessible by such a simple isolation process, it is usually used as scaffold for further derivatization.
- the present disclosure provides a process for increasing the proportion of the 7 ⁇ -epimer in an 7 ⁇ /7 ⁇ -epimer mixture of a 7-substituted 6 ⁇ ,14 ⁇ -ethenomorphinan or a 7-substituted 6 ⁇ ,14 ⁇ -ethanomorphinan, said process comprising: contacting a solution of the 7 ⁇ /7 ⁇ -epimer mixture with an acid to provide a precipitate, and isolating the precipitate to provide an isolated precipitate and a mother liquor.
- the process of the present invention increases the proportion of the 7 ⁇ -epimer in an 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula I : wherein:
- the 7 ⁇ -epimer and the 7 ⁇ -epimer of compounds of Formula I can be represented as Formulae I b and I a , respectively:
- the process of the present invention increases the proportion of the 7 ⁇ -epimer in an 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula II : wherein:
- the isolated precipitate contains an increased proportion of the 7 ⁇ -epimer as a salt relative to the 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula II.
- the proportion of the 7 ⁇ -epimer in the isolated precipitate is at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
- the process of the present invention increases the proportion of the 7 ⁇ -epimer in an 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula III : wherein:
- an increased proportion of the 7 ⁇ -epimer salt, relative to the 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula III can be found in the isolated precipitate or in the mother liquor depending on the conditions (i.e., the acid and/or the solvent) of the precipitation.
- the isolated precipitate contains an increased proportion of the 7 ⁇ -epimer as a salt relative to the 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula III .
- the proportion of the 7 ⁇ -epimer in the isolated precipitate is at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
- the mother liquor contains an increased proportion of the 7 ⁇ -epimer as a salt relative to the 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula III .
- the proportion of the 7 ⁇ -epimer in the mother liquor is at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
- the present disclosure provides a process for purifying the 7 ⁇ -epimer from an 7 ⁇ /7 ⁇ -epimer mixture of a 7-substituted 6 ⁇ ,14 ⁇ -ethenomorphinan or a 7-substituted 6 ⁇ ,14 ⁇ -ethanomorphinan.
- Said process comprisises contacting a solution of the 7 ⁇ /7 ⁇ -epimer mixture with an acid under conditions conducive to precipitation of the 7 ⁇ -epimer, and isolating the precipitate.
- the proportion of the 7 ⁇ -epimer as a salt in the isolated precipitate relative to the 7 ⁇ /7 ⁇ -epimer mixture is at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
- the process comprises purifying the 7 ⁇ -epimer from an 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula I.
- the process comprises purifying the 7 ⁇ -epimer from an 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula II.
- the process comprises purifying the 7 ⁇ -epimer from an 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula III .
- the 7 ⁇ /7 ⁇ -epimer mixture used in the processes of the present invention can be, for example, the reaction mixture after the Diels-Alder reaction (e.g., the mother liquor obtained after the first precipitate is filtered off), the reaction mixture after further functionalization of the ketone group (e.g., after the reaction with a Grignard reagent), or the reaction mixture after the hydrogenation of the double bond.
- the 7 ⁇ /7 ⁇ -epimer mixture used in the processes of the present invention is the product of the epimerization of the first precipitate or the mother liquor obtained after the salt formation.
- the reaction mixture prior to contacting with the acid, the reaction mixture is typically concentrated, and then any precipitation is dissolved by optionally adding a solvent and by heating to obtain a solution.
- the mother liquor is concentrated to dryness and the residue is redissolved in a solvent at an elevated temperature to obtain a solution before adding the acid.
- the 7 ⁇ /7 ⁇ -epimer mixture can be an isolated precipitate that is further purified with respect to the 7 ⁇ -epimer by the processes of the present invention.
- the 7 ⁇ /7 ⁇ -epimer mixture is first dissolved in a solvent at an elevated temperature to obtain a solution of the 7 ⁇ /7 ⁇ -epimer mixture before adding the acid.
- the solution of the 7 ⁇ /7 ⁇ -epimer mixture is contacted with the acid at about room temperature. In another embodiment, the solution of the 7 ⁇ /7 ⁇ -epimer mixture is contacted with the acid at about 50 °C to about the boiling point of the solution.
- the temperature of the solution is from about 55 °C to the reflux temperature of the solvent, and more preferably the temperature of the solution is from about 60 °C to the reflux temperature of the solvent. In another embodiment, the temperature of the solution of the 7 ⁇ /7 ⁇ -epimer mixture is from about 55 °C to about 80 °C, and more preferably the temperature is from about 60 °C to about 80 °C.
- Suitable solvents to be used in the process of the present invention include, for example, aliphatic alcohols, aromatic solvents, ethers (such as aliphatic ethers or THF), and acetonitrile, or combinations thereof.
- the solvent is an aliphatic alcohol, an aromatic solvent, and aliphatic ether, or combinations thereof.
- the solvent is an aliphatic alcohol or mixtures thereof.
- Suitable aliphatic alcohols include C 1-6 alcohols, such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, n-pentanol, and n-hexanol, and preferably methanol, ethanol, n-propanol, and iso-propanol, and preferally iso-propanol.
- the solvent is an aromatic solvent.
- Suitable aromatic solvents include, for example, toluene, xylene and benzene, and preferably toluene.
- the solvent is an aliphatic ether.
- Suitable aliphatic ethers include, for example, C 5-6 cycloalkyl(C 1-6 )alkyl ethers, such as cyclopentyl methyl ether.
- the solvent in the processes of the present invention is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, toluene, and cyclopropyl methyl ether, or the solvent can be a combination (i.e., a mixture) of these solvents.
- the solution of the 7 ⁇ /7 ⁇ -epimer mixture is contacted with the acid either at the elevated temperature or after cooling it, for example, to room temperature.
- the solution of the 7 ⁇ /7 ⁇ -epimer mixture is contacted with the acid at an elevated temperature and then the mixture is cooled to form a precipitate.
- the solution of the 7 ⁇ /7 ⁇ -epimer mixture is contacted with the acid, for example, by simply adding, preferably portion wise (or dropwise when dissolved in a suitable solvent), a sufficient amount of the acid to the solution and mixing.
- the sufficient amount of the acid is an amount that is necessary for converting the 7 ⁇ -epimer of the 7 ⁇ /7 ⁇ -epimer mixture into its salt.
- the amount of the acid is from about 0.5 to about 1.5 equivalents based on the amount of the 7 ⁇ -epimer. In another embodiment, the amount of the acid is from about 0.8 to about 1.3 equivalents, preferably from about 0.9 to about 1.2 equivalents, and more preferably about 1.0 or about 1.1 equivalents based on the amount of the 7 ⁇ -epimer.
- the amount of the 7 ⁇ -epimer of the 7-substituted 6 ⁇ ,14 ⁇ -ethenomorphinan or the 7-substituted 6 ⁇ ,14 ⁇ -ethanomorphinan can be determined by conventional methods described in the art, such as, for example by 1 H NMR: interation of the H-5 protons, as described in Uff et al., Magnetic Resonance in Chemistry 23:6 (1985 ); Marton, J., et al., Acta Chemica Scandinavia 52:1234-1238 (1998 ); and Derrick, I., et al., Tetrahedron Letters 41:7571-7576 (2000 ), and by HPLC as described in the examples.
- the proportion of the 7 ⁇ -epimer in the 7 ⁇ /7 ⁇ -epimer mixture is at least about 20%. In another embodiment, the proportion of the 7 ⁇ -epimer in the 7 ⁇ /7 ⁇ -epimer mixture is at least about 50%.
- the acid is an achiral acid. In another embodiment, the acid is a chiral acid.
- the acid is selected from the group consisting of an aliphatic monocarboxylic acid and an aliphatic dicarboxylic acid, or a combination thereof, any of which is optionally substituted.
- the acid is an optionally substituted, saturated or unsaturated aliphatic monocarboxylic acid, and preferably a saturated or unsaturated C 1-6 aliphatic monocarboxylic acid optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen and hydroxy.
- the acid is a saturated, unsubstituted C 1-4 aliphatic monocarboxylic acid, or a saturated C 1-4 aliphatic monocarboxylic acid substituted with 1, 2 or 3 substituents, each independently selected from the group consisting of fluoro, chloro, bromo, iodo, and hydroxy.
- the monocarboxylic acid is selected from the group consisting of acetic acid, trifluoroacetic acid (TFA), trichloroacetic acid, and tribromoacetic acid, and preferably TFA.
- the acid is an optionally substituted, saturated or unsaturated aliphatic dicarboxylic acid, and preferably a saturated C 2-6 aliphatic dicarboxylic acid optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen and hydroxy.
- the acid is an unsaturated C 2-6 aliphatic dicarboxylic acid optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen and hydroxy, and preferably an unsaturated, unsubstituted C 2-6 aliphatic dicarboxylic acid.
- the dicarboxylic acid is fumaric acid or maleic acid.
- the precipitate can be isolated by any conventional separation process. Suitable separation processes for isolating the precipitate include, for example, filtration, such as vacuum filtration, and centrifugal separations. Preferably, the precipitate is isolated by filtration, and the filter cake is optionally washed to remove any residual mother liquor.
- G in compounds of any of Formulae I-III is R 1 .
- R 1 is hydrogen
- R 1 is alkyl, alkenyl, or alkynyl, and specifically C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl.
- R 1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso-butyl, or sec-butyl, and advantageously R 1 is methyl.
- R 1 is ethenyl, propenyl, isopropenyl, butenyl, or sec-butenyl.
- R 1 is ethynyl, propynyl, butynyl, or 2-butynyl.
- R 1 is (cycloalkyl)alkyl, (heterocyclo)alkyl, arylalkyl, or heteroarylalkyl, wherein the cycloalkyl, heterocyclo, aryl, or heteroaryl portions thereof are optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, carboxy, alkoxy, alkylcarbonyl, and alkoxycarbonyl.
- Suitable (cycloalkyl)alkyl groups for R 1 include C 3-7 cycloalkyl(C 1-4 )alkyl groups, and specifically C 3-6 cycloalkyl(C 1-4 )alkyl groups, wherein the cycloalkyl portion is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, carboxy, alkoxy, alkylcarbonyl, and alkoxycarbonyl.
- R 1 is cyclopropyl(C 1-4 )alkyl, cyclobutyl(C 1-4 )alkyl, cyclopentyl(C 1-4 )alkyl, or cyclohexyl(C 1-4 )alkyl, optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, carboxy, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
- R 1 is unsubstituted (cyclopropyl)methyl, 2-(cyclopropyl)ethyl or 3-(cyclopropyl)propyl.
- Suitable (heterocyclo)alkyl groups for R 1 include 5- or 6-membered heterocyclo(C 1-4 )alkyl, wherein the heterocyclo portion is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, carboxy, alkoxy, alkylcarbonyl, and alkoxycarbonyl; and typically optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, carboxy, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
- R 1 is unsubstituted 5- or 6-membered heterocyclo(C 1-4 )alkyl, such as tetrahydrofuranyl(C 1-4 )alkyl.
- Suitable arylalkyl groups for R 1 include aryl(C 1-4 )alkyl groups wherein the aryl portion is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, carboxy, alkoxy, alkylcarbonyl, and alkoxycarbonyl; and typically optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, carboxy, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
- R 1 is C 6-10 aryl(C 1-4 )alkyl substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, carboxy, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
- R 1 is benzyl, phenethyl, or naphthylmethyl substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, methyl, ethyl, fluorine, bromine, iodine, chlorine, trifluoromethyl, carboxy, methoxy, ethoxy, methylcarbonyl, ethylcarbonyl, methoxycarbonyl, and ethoxycarbonyl.
- R 1 is unsubstituted C 6-10 aryl(C 1-4 )alkyl, such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, 3-naphthylpropyl, and 4-naphthylbutyl; typically benzyl and phenethyl, and especially benzyl.
- aryl(C 1-4 )alkyl such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl, 2-naphthylethyl, 3-naphthylpropyl, and 4-naphthylbutyl; typically benzyl and phenethyl, and especially benzyl.
- Suitable heteroarylalkyl groups for R 1 include heteroaryl(C 1-4 )alkyl groups wherein the heteroaryl portion is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, carboxy, alkoxy, alkylcarbonyl, and alkoxycarbonyl; and typically optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, carboxy, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
- R 1 is 5- or 6-membered heteroaryl(C 1-4 )alkyl, such as furanyl(C 1-4 )alkyl, substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, carboxy, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl; and typically each independently selected from the group consisting of hydroxy, halo, halo(C 1-2 )alkyl, carboxy, C 1-2 alkoxy, C 1-2 alkylcarbonyl, and C 1-2 alkoxycarbonyl.
- R 2 in compounds of any of Formulae I-III is hydrogen, cyano, alkylcarbonyl, alkoxycarbonyl, or carboxamido.
- typically R 2 is hydrogen, cyano, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, -CONH 2 , -CON(H)C 1-4 alkyl, -CON(C 1-4 alkyl) 2 , or -CON(H)Ph.
- R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl, (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl.
- Useful compounds include those where R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 5- or 6-membered heterocyclo, aryl, 5- or 6-membered heteroaryl, C 3-7 cycloalkyl(C 1-4 )alkyl, C 3-7 cycloalkenyl(C 1-4 )alkyl, 5- or 6-membered heterocyclo(C 1-4 )alkyl, aryl(C 1-4 )alkyl, 5- or 6-membered heteroaryl(C 1-4 )alkyl, aryl(C 1-4 )alkoxycarbonyl, or 5- or 6-membered heteroaryl(C 1-4 )alkoxycarbonyl, any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, al
- R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 5- or 6-membered heterocyclo, C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-7 (cycloalkyl)(C 1-4 )alkyl, C 3-7 (cycloalkenyl)(C 1-4 )alkyl, 5- or 6-membered heterocyclo(C 1-4 )alkyl, C 6-10 aryl(C 1-4 )alkyl, 5- or 6-membered heteroaryl(C 1-4 )alkyl, C 6-10 aryl(C 1-4 )alkoxycarbonyl, or 5- or 6-membered heteroaryl(C 1-4 )alkoxycarbonyl, any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo
- R 2 is C 3-7 (cycloalkyl)(C 1-4 )alkyl or C 3-7 (cycloalkenyl)(C 1-4 )alkyl, and especially C 3-7 (cycloalkyl)(C 1-4 )alkyl, such as cyclopropyl(C 1-4 )alkyl, cyclobutyl(C 1-4 )alkyl, cyclopentyl(C 1-4 )alkyl, or cyclohexyl(C 1-4 )alkyl, optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl, and especially optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, methyl, ethyl, halo, tri
- R 3 in compounds of Formula I or R 31 in compounds of Formula II is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 5- to 6-membered heterocyclo, C 6-12 aryl, 5- to 10-membered heteroaryl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 cycloalkyl(C 2-6 )alkenyl, C 3-7 cycloalkenyl(C 1-6 )alkyl, C 3-7 cycloalkenyl(C 2-6 )alkenyl, 5- to 6-membered heterocyclo(C 1-4 )alkyl, 5- to 6-membered heterocyclo(C 2-4 )alkenyl, C 6-12 aryl(C 1-6 )alkyl, C 6-12 aryl(C 2-6 )alkenyl, 5- to 10-member
- R 3 is C 1-6 alkylcarbonyl, which is unsubstituted or substituted with 1, 2, or 3 substituents, each independently seletcted from the group consisting of hydroxy, alkyl, hydroxy(C 1-6 )alkyl, halo, halo(C 1-6 )alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, and C 1-6 alkoxycarbonyl.
- R 4 in compounds of any of Formulae I-III is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 5- to 6-membered heterocyclo, C 6-12 aryl, 5- to 10-membered heteroaryl, C 3-7 cycloalkyl(C 1-6 )alkyl, C 3-7 cycloalkyl(C 2-6 )alkenyl, C 3-7 cycloalkenyl(C 1-6 )alkyl, C 3-7 cycloalkenyl(C 2-6 )alkenyl, 5- to 6-membered heterocyclo(C 1-6 )alkyl, 5- to 6-membered heterocyclo(C 2-6 )alkenyl, C 6-12 aryl(C 1-6 )alkyl, C 6-12 aryl(C 2 - 6 )alkenyl, 5- to 10-
- the 7 ⁇ -epimer of compounds of any of Formulae I-II is represented by Formula IV: wherein R 1 , R 2 , R 4 , G, and are as defined above for Formula I, and R 5 is H or C 1-6 alkyl, which is unsubstituted or substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, hydroxy(C 1-4 )alkyl, halo, halo(C 1-4 )alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, and C 1-6 alkoxycarbonyl.
- the 7 ⁇ /7 ⁇ -epimer mixture of a compound of Formula I is represented by Formula V: wherein R 1 , R 2 , R 4 , and G are as defined above for Formula I , and R 5 is C 1-6 alkyl, which is unsubstituted or substituted with 1, 2, or 3 substituents, each independently selected form the group consisting of hydroxy, hydroxy(C 1-4 )alkyl, halo, halo(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl.
- R 1 is hydrogen, C 1-6 alkyl, or benzyl
- R 2 is C 2-6 alkenyl, cyclopropyl(C 1-4 )alkyl, cyclobutyl(C 1-4 )alkyl, cyclopentyl(C 1-4 )alkyl, or cyclohexyl(C 1-4 )alkyl, optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, C 1-4 alkoxy, C 1-4 alkylcarbonyl, and C 1-4 alkoxycarbonyl; and R 4 is hydrogen or C 1-6 alkyl.
- R 2 is unsubstituted C 2-6 alkenyl or unsubstituted cyclopropyl(C 1-4 )alkyl. In another embodiment, R 2 is (cyclopropyl)methyl. In another embodiment, R 1 is hydrogen, C 1-6 alkyl, or benzyl. In another embodiment, R 2 is (cyclopropyl)methyl.
- G in compounds of any of Formulae I-V is a hydroxyl protecting group PG.
- Suitable hydroxyl protecting groups for PG are well known and include, for example, any suitable hydroxyl protecting group disclosed in Wuts, P. G. M. & Greene, T. W., Greene's Protective Groups in Organic Synthesis, 4rd Ed., pp. 16-430 (J. Wiley & Sons, 2007 ).
- hydroxyl protecting group refers to group that blocks (i.e., protects) the hydroxy functionality while reactions are carried out on other functional groups or parts of the molecule.
- Those skilled in the art will be familiar with the selection, attachment, and cleavage of protecting groups and will appreciate that many different protective groups are known in the art, the suitability of one protective group or another being dependent on the particular the synthetic scheme planned.
- Suitable hydroxyl protecting groups are generally able to be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds. These protecting groups can be introduced or removed at a convenient stage using methods known in the art. The chemical properties of such groups, methods for their introduction and removal are known in the art and can be found, for example, in Greene, T.W. and Wuts, P.G.M., above. Additional hydroxy protecting groups can be found, for example, in U.S. Patent No. 5,952,495 , U.S. Patent Appl. Pub. No. 2008/0312411 , WO 2006/035195 , and WO 98/02033 .
- Suitable hydroxyl protecting groups include the methoxymethyl, tetrahydropyranyl, tert-butyl, allyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, acetyl, pivaloyl, benzoyl, benzyl (Bn), and p-methoxybenzyl group.
- R 1 and PG are overlapping, such as tert-butyl, benzyl, etc., and, thus, certain compounds of Formulae I-V having R 1 groups that act as hydroxyl protecting groups can be pharmaceutically active.
- the hydroxyl protecting group PG is selected from the group consisting of alkyl, arylalkyl, heterocyclo, (heterocyclo)alkyl, acyl, silyl, and carbonate, any of which are optionally substituted.
- the hydroxyl protecting group is an alkyl group, typically an optionally substituted C 1-6 alkyl group, and suitably unsubstituted methyl or tert-butyl.
- the hydroxyl protecting group PG is an arylalkyl group.
- Suitable arylalkyl groups include, for example, an unsubtituted benzyl group, substituted benzyl groups, such as p-methoxybenzyl, and naphthylmethyl.
- the hydroxyl protecting group PG is a heterocyclo group, such as unsubstituted tetrahydropyranyl or optionally substituted tetrahydropyranyl.
- the hydroxyl protecting group PG is a silyl group.
- silyl refers to the following group having the structure: wherein R 6 , R 7 , and R 8 are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl, any of which is optionally substituted.
- the silyl group is trimethyl silyl, tert-butyldimethyl silyl, tert-butyldiphenyl silyl, or tri-isopropyl silyl.
- the hydroxyl protecting group PG is an acyl group.
- acyl as employed herein refers to the following structure: wherein R 9 is alkyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl, any of which is optionally substituted.
- the acyl group can be, for example, C 1-4 alkylcarbonyl (such as, for example, acetyl), arylcarbonyl (such as, for example, benzoyl), levulinoyl, or pivaloyl.
- the acyl group is benzoyl.
- the hydroxyl protecting group is a carbonate group.
- carbonate refers to the following structure: wherein R 10 is alkyl, alkenyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl, any of which is optionally substituted.
- R 10 is C 1-10 alkyl (e.g., 2,4-dimethylpent-3-yl), C 2-6 alkenyl (e.g., ethenyl or prop-2-enyl, i.e., allyl), C 3-12 cycloalkyl (e.g., adamantyl), phenyl, or benzyl.
- the hydroxyl protecting group is a carbamate group.
- carbamate refers to the following structure: wherein R 11 is alkyl, alkenyl, cycloalkyl, aryl, (cycloalkyl)alkyl, or arylalkyl, any of which is optionally substituted.
- R 11 is C 1-10 alkyl (e.g., tert-butyl, 2,4-dimethylpent-3-yl), C 2-6 alkenyl (e.g., ethenyl or prop-2-enyl, i.e., allyl), C 3-12 cycloalkyl (e.g., adamantyl), phenyl, or benzyl.
- C 1-10 alkyl e.g., tert-butyl, 2,4-dimethylpent-3-yl
- C 2-6 alkenyl e.g., ethenyl or prop-2-enyl, i.e., allyl
- C 3-12 cycloalkyl e.g., adamantyl
- phenyl or benzyl.
- the present invention also pertains to the preparation of 7 ⁇ -substituted compounds of Formula I b : and the salts thereof, wherein G and R 2 -R 4 are as defined above for Formula I, comprising:
- the second mother liquor and/or the first precipitate are optionally epimerized and processed according to step d) above.
- the present invention also pertains to the preparation of 7 ⁇ -substituted compounds of Formula V b : and the salts thereof, wherein
- the proportion of the 7 ⁇ -epimer in the first mother liquor obtained from the Diels-Alder reaction is at least about 10%, at leat about 15%, at least about 20%, or at least about 25%.
- the first precipitate typically forms upon cooling the Diels-Alder reaction mixture and contains the 7 ⁇ -epimer as the major product.
- the first precipitate can be isolated by, e.g., filtration, such as vacuum filtration, or centrifugal separators.
- the first mother liquor is partially concentrated, e.g., by evaporation, after the isolation of the first precipitate of the 7 ⁇ /7 ⁇ -epimer mixture.
- the first mother liquor is heated to dissolve any precipitate of the 7 ⁇ /7 ⁇ -epimer mixture and to obtain a solution containing the 7 ⁇ /7 ⁇ -epimer mixture.
- one or more additional solvents can be added to the first mother liquor.
- the first mother liquor is concentrated to dryness and the residue is redissolved in a solvent to obtain a solution.
- solvents are those described above in connection with Formula I, and are typically selected from the group consisting of aliphatic alcohols, aromatic solvents, aliphatic ethers, and combinations thereof.
- the solvent is iso-propanol (IPA).
- the partially concentrated first mother liquor including the optional additional solvent, or the solution obtained from the residue are heated to a temperature of about 50 °C to about the boiling point of the solution.
- the temperature is from about 55 °C to the reflux temperature of the solvent, and more preferably the temperature is from about 60 °C to the reflux temperature of the solvent.
- the temperature is from about 55 °C to about 80 °C, and more preferably the temperature is from about 60 °C to about 80 °C.
- solvent herein, includes mixtures/combinations of one or more solvents.
- the heated first mother liquor is then contacted with an acid to obtain a second precipitate.
- the heated mother liquor is first cooled down, for example to room temperature, and then contacted with the acid to obtain the second precipitate.
- Suitable and preferable acids are those described above in connection with the processes for increasing the proportion of the 7 ⁇ -epimer and purifying the 7 ⁇ -epimer.
- the acid is TFA.
- the amount of the acid used is from about 0.5 to about 1.5 equivalents based on the amount of the 7 ⁇ -epimer.
- the acid is used in an amount of from about 0.8 to about 1.3 equivalents, preferably from about 0.9 to about 1.2 equivalents, and more preferably about 1.0 or about 1.1 equivalents based on the amount of the 7 ⁇ -epimer.
- the second precipitate can be isolated by, e.g., vacuum filtration or centrifugal separators.
- the proportion of the 7 ⁇ -epimer in the second precipitate is at least about 60%, at least about 70%, at least about 80%, or at least about 90%.
- the salts formed in the processes of the present invention can be converted to their free bases by methods known in the art and by the methods described in the examples.
- the mother liquor obtained after isolating the second precipitate (the second mother liquor) is enriched with the 7 ⁇ -epimer, which can be epimerized, for example, by reacting with potassium carbonate (K 2 CO 3 ) or diazabicycloundec-7-ene (DBU), and then repeating the process as described above to obtain a further second precipitate of the 7 ⁇ -epimer.
- the epimerization can be conducted, for example, as described by Marton, J., et al., Acta Chemica Scandinavia 52:1234-1238 (1998 ), and Derrick, I., et al., Tetrahedron Letters 41:7571-7576 (2000 ).
- the first precipitate is also enriched with the 7 ⁇ -epimer.
- This can be epimerized as described above by reacting with, for example, potassium carbonate (K 2 CO 3 ) or diazabicycloundec-7-ene (DBU), and then repeating the process as described above to obtain a further second precipitate of the 7 ⁇ -epimer.
- K 2 CO 3 potassium carbonate
- DBU diazabicycloundec-7-ene
- Optional substituents attached to aryl, phenyl and heteroaryl rings each take the place of a hydrogen atom that would otherwise be present in any position on the aryl, phenyl or heteroaryl rings.
- Useful halo or halogen groups include fluorine, chlorine, bromine and iodine.
- Useful alkyl groups are selected from straight-chain and branched-chain C 1-10 alkyl groups.
- Typical C 1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, tert-butyl, iso -butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, nonyl and decyl, among others.
- useful alkyl groups are selected from straight chain C 1-6 alkyl groups and branched chain C 3-6 alkyl groups.
- Typical C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, tert-butyl, iso -butyl, pentyl, 3-pentyl, hexyl, among others.
- useful alkyl groups are selected from straight chain C 2-6 alkyl groups and branched chain C 3-6 alkyl groups.
- Typical C 2-6 alkyl groups include ethyl, propyl, isopropyl, butyl, sec-butyl, tert -butyl, iso -butyl, pentyl, 3-pentyl, hexyl among others.
- useful alkyl groups are selected from straight chain C 1-4 alkyl groups and branched chain C 3-4 alkyl groups.
- Typical C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec -butyl, tert-butyl, iso -butyl.
- Useful cycloalkyl groups are selected from saturated cyclic hydrocarbon groups containing one to three rings having from three to twelve carbon atoms ( i.e., C 3 -C 12 cycloalkyl) or the number of carbons designated.
- the cycloalkyl has one or two rings.
- the cycloalkyl is a C 3 -C 8 cycloalkyl.
- Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl and the like.
- Useful cycloalkenyl groups are selected from partially unsaturated (containing one or two double bonds) cyclic hydrocarbon groups containing one to three rings having from four to twelve carbon atoms ( i.e ., C 4 -C 12 cycloalkenyl) or the number of carbons designated.
- the cycloalkenyl has one or two rings.
- the cycloalkenyl is a C 3 -C 8 cycloalkyl.
- the cycloalkenyl group contains one double bond.
- Exemplary cycloalkenyl groups containing one double bond include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, among others.
- the cycloalkenyl group contains two double bonds.
- the cycloalkenyl groups containing two double bonds have from five to twelve carbon atoms (i.e., C 5 -C 12 cycloalkadienyl).
- Exemplary cycloalkenyl groups having two double bonds include cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl, cyclononadienyl, cyclodecadienyl, among others.
- Useful alkenyl groups are selected from straight-chain and branched-chain C 2-6 alkenyl groups, preferably C 2-4 alkenyl.
- Typical C 2-6 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec -butenyl, pentenyl, and hexenyl.
- Typical C 2-4 alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and sec-butenyl.
- Useful alkynyl groups are selected from straight-chain and branched-chain C 2-6 alkynyl groups, preferably C 2-4 alkynyl.
- Typical C 2-6 alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
- Typical C 2-4 alkynyl groups include ethynyl, propynyl, butynyl, and 2-butynyl groups.
- Useful haloalkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted by one or more fluorine, chlorine, bromine or iodine atoms (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups).
- fluorine, chlorine, bromine or iodine atoms e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl
- Useful hydroxyalkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted by one or more hydroxy groups, such as monohydroxyalkyl and dihydroxyalkyl groups (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxypentyl groups, and especially 2-hydroxy-3,3-dimethylbut-2-yl, 2-hydroxypent-2-yl, 2-hydroxyprop-2-yl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl).
- monohydroxyalkyl and dihydroxyalkyl groups e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxypentyl groups
- Useful alkoxy groups include oxygen substituted by one of the C 1-10 alkyl groups mentioned above (e.g., methoxy, ethoxy, propoxy, iso-propoxy, butoxy, tert-butoxy, iso-butoxy, sec-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy).
- Useful alkoxyalkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted with any of the above-mentioned alkoxy groups (e.g., methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, propoxymethyl, iso-propoxymethyl, 2-propoxyethyl, 3-propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl).
- alkoxy groups e.g., methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, propoxymethyl, iso-propoxymethyl, 2-propoxyethyl, 3-
- Useful haloalkoxy groups include oxygen substituted by one of the C 1-10 haloalkyl groups mentioned above (e.g., fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy).
- Useful (cycloalkyl)alkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted with any of the above-mentioned cycloalkyl groups (e.g., (cyclopropyl)methyl, 2-(cyclopropyl)ethyl, (cyclopropyl)propyl, (cyclobutyl)methyl, (cyclopentyl)methyl, (cyclohexyl)methyl, and the like).
- Useful (cycloalkyl)alkenyl groups include any of the above-mentioned C 2-6 alkenyl groups substituted with any of the above-mentioned cycloalkyl groups.
- Useful (cycloalkenyl)alkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted with any of the above-mentioned cycloalkenyl groups (e.g., (cyclobutenyl)methyl, 2-(cyclobutenyl)ethyl, (cyclobutenyl)propyl, (cyclopentenyl)methyl, (cyclohexenyl)methyl, (cyclopentadienyl)methyl, and the like).
- cycloalkenyl groups e.g., (cyclobutenyl)methyl, 2-(cyclobutenyl)ethyl, (cyclobutenyl)propyl, (cyclopentenyl)methyl, (cyclohexenyl)methyl, (cyclopentadienyl)methyl, and the like).
- Useful (cycloalkenyl)alkenyl groups include any of the above-mentioned C 2-6 alkenyl groups substituted with any of the above-mentioned cycloalkenyl groups.
- Useful aryl groups are C 6-14 aryl, preferably C 6-12 aryl, and especially C 6-10 aryl.
- Typical C 6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups, more preferably phenyl, naphthyl, and biphenyl groups.
- Useful aryloxy groups include oxygen substituted by one of the aryl groups mentioned above (e.g., phenoxy).
- Useful arylalkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted by any of the above-mentioned aryl groups (e.g., benzyl, phenethyl, and the like).
- Useful (arylalkyl)carbonyl groups include a carbonyl group sunbstituted by any of the above-mentioned arylalkyl groups.
- Useful aralkyloxy or arylalkoxy groups include oxygen substituted by one of the above-mentioned arylalkyl groups (e.g., benzyloxy).
- Useful (arylalkoxy)carbonyl groups include a carbonyl group sunbstituted by any of the above-mentioned arylalkoxy groups (e.g., (benzyloxy)carbonyl).
- heteroaryl or “heteroaromatic” as employed herein refers to groups having 5 to 14 ring atoms, with 6, 10 or 14 ⁇ electrons shared in a cyclic array, and containing carbon atoms and 1, 2, or 3 oxygen, nitrogen or sulfur heteroatoms, or 4 nitrogen atoms.
- heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2 H -pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3 H -indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4a H -carbazolyl, carbazolyl, ⁇ -carbolinyl,
- Typical heteroaryl groups include thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g.,pyrrol-1-yl, 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., imidazol-1-yl, 1H-imidazol-2-yl and 1H-imidazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl and tetrazol-5-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyr
- Useful heteroarylalkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted by any of the above-mentioned heteroaryl groups (e.g., (thien-2-yl)methyl, 2-furylmethyl, (pyrrol-1-yl)methyl, 2-(1H-pyrrol-2-yl)ethyl and the like).
- Useful heteroarylalkenyl groups include any of the above-mentioned C 2-6 alkenyl groups substituted by any of the above-mentioned heteroaryl groups.
- Useful heteroarylalkoxy groups include oxygen substituted by one of the above-mentioned heteroaryl groups.
- Useful (heteroarylalkoxy)carbonyl groups include a carbonyl group sunbstituted by any of the above-mentioned heteroarylalkoxy groups.
- heterocyclic and “heterocyclo” are used herein to mean saturated or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consist of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on a carbon atom or on a nitrogen atom if the resulting compound is stable.
- the 3- to 7-membered monocyclic heterocyclic ring is either a saturated, or unsaturated nonaromatic ring.
- a 3-membered heterocyclo can contain up to 1 heteroatom
- a 4-membered heterocyclo can contain up to 2 heteroatoms
- a 5-membered heterocyclo can contain up to 4 heteroatoms
- a 6-membered heterocyclo can contain up to 4 heteroatoms
- a 7-membered heterocyclo can contain up to 5 heteroatoms.
- Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
- the 3- to 7-membered heterocyclo can be attached via a nitrogen or carbon atom.
- a 7- to 10-membered bicyclic heterocyclo contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
- the 7- to 10-membered bicyclic heterocyclo can be attached via a nitrogen or carbon atom.
- heterocyclic rings include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, 2-oxooxazolidinyl, tetrahydrothienyl, imidazolidinyl, hexahydropyrimidinyl, benzodiazepines, and the like.
- Useful (heterocyclo)alkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted by any of the above-mentioned heterocyclic groups (e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-l-yl)methyl, (piperidin-l-yl)methyl, (morpholin-l-yl)methyl, (2-oxooxazolidin-4-yl)methyl, 2-(2-oxooxazolidin-4-yl)ethyl, (2-oxo-imidazolidin-1-yl)methyl, (2-oxo-imidazolidin-1-yl)ethyl, (2-oxo-imidazolidin-1-yl)propyl, and the like).
- heterocyclic groups e.g., (pyrrolidin-2-yl)methyl, (pyrrolidin-l-yl)methyl, (piperidin-l-yl)methyl, (morpholin-
- Useful (heterocyclo)alkenyl groups include any of the above-mentioned C 2-6 alkenyl groups substituted by any of the above-mentioned heterocyclic groups.
- Useful arylcarbonyl groups include a carbonyl group substituted by any of the above-mentioned aryl groups (e.g., benzoyl).
- Useful alkylcarbonyloxy or acyloxy groups include oxygen substituted by one of the above-mentioned alkylcarbonyl groups.
- Useful alkylcarbonylamino or acylamino groups include any of the above-mentioned alkylcarbonyl groups attached to an amino nitrogen, such as methylcarbonylamino.
- exemplary carboxamido groups include -CONH 2 , -CON(H)CH 3 , -CON(CH 3 ) 2 , and -CON(H)Ph and the like
- Useful alkylaminocarbonyl and dialkylaminocarbonyl groups are any of the above-mentioned carboxamido groups, where R 11 is H and R 12 is C 1-10 alkyl or where R 13 and R 14 are each independently selected from a C 1-10 alkyl group, respectively.
- sulfonamido refers to a radical of formula -SO 2 NR 11 R 12 , wherein R 11 and R 12 are each independently hydrogen, optionally substituted C 1-10 alkyl, or optionally substituted aryl.
- exemplary sulfonamido groups include -SO 2 NH 2 , -SO 2 N(H)CH 3 , -SO 2 N(H)Ph and the like.
- Useful mercaptoalkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted by a -SH group.
- Useful carboxyalkyl groups include any of the above-mentioned C 1-10 alkyl groups substituted by -COOH.
- hydroxyl or “hydroxy” refer to -OH.
- cyano refers to -CN.
- zido refers to -N 3 .
- mother liquor means the part of a solution that is left over after crystallization.
- ambient temperature means the temperature of the surroundings.
- the ambient temperature indoors is the same as room temperature, which is from about 20 °C to about 25 °C.
- the term "optionally substituted” refers to a group that may be unsubstituted or substituted.
- Optional substituents on optionally substituted groups when not otherwise indicated, include one or more groups, typically 1, 2, or 3 groups, independently selected from the group consisting of halo, halo(C 1-6 )alkyl, aryl, heterocycle, cycloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl(C 1-6 )alkyl, aryl(C 2-6 )alkenyl, aryl(C 2-6 )alkynyl, cycloalkyl(C 1-6 )alkyl, heterocyclo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, carboxy(C 1-6 )alkyl, alkoxy(C 1-6 )alkyl, nitro, ureido, cyano, alkylcarbonylamino, hydroxy, thiol, alkylcarbonyloxy, aryloxy, ar(C 1-6 )alkyloxy
- Preferred optional substituents include halo, halo(C 1-6 )alkyl, hydroxy(C 1-6 )alkyl, hydroxy, nitro, C 1-6 alkyl, C 1-6 alkoxy, and halo(C 1-6 )alkoxy.
- Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, such as epimers.
- the present invention is meant to encompass the uses of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
- the individual enantiomers may be separated according to methods known to those of ordinary skill in the art in view of the present disclosure.
- the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.
- under conditions conducive to precipitation refers to conditions which are suitable to induce or facilitate precipitation of the desired compound.
- stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
- chiral center refers to a carbon atom to which four different groups are attached.
- chiral in the context of the present invention also refers to a compound of group, exhibiting a “chiral center", such as a chiral acid.
- exemplary chiral acids are lactic acid, tartric acid, and the like.
- achiral in the context of the presnt invention refers to a compound of group, wherein no “chiral center” is present.
- An example for achiral compounds are achiral acids, such as acetic acid, trifluoroacetic acid, tribromoacetic acid, trichloroacetic acid, fumaric acid, maleic acid, and the like.
- epimer refers to diastereomers that have opposite configuration at only one of two or more tetrahedral streogenic centres present in the respective molecular entities.
- stereoisomer is an atom, bearing groups such that an interchanging of any two groups leads to a stereoisomer.
- enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
- racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
- resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
- Compounds of Formula I can be prepared as shown in the schemes below.
- the synthesis of the compounds usually starts with a Diels-Alder reaction of thebaine or oripavine with dienophile, for example, a vinyl ketone under formation of the 7 ⁇ /7 ⁇ -epimer mixture A-2 (7 ⁇ -epimer A a -2 and 7 ⁇ -epimer A b - 2 ) (Scheme 2).
- G is R 1 or a hydroxyl protecting group as defined above for Formula I and R is alkyl, optionally substituted with 1, 2, or 3, substituents each independently selected from the group consisting of hydroxy, hydroxyalkyl, halo, haloalkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl, respectively, or a functional group that can be converted to these groups.
- the 7 ⁇ /7 ⁇ -epimer mixture of compounds of Formula I i.e., the mixture of epimers A a - 2 and A b - 2
- the mixture of epimers A a - 2 and A b - 2 can be synthesized by methods described in the art, for example, in Marton J., et al., Synthetic Communications 25(6):829-848 (1995 ) and Bentley, K. W., Journal of American Chemical Society 89(13):3267-3273 (1967 ).
- the alpha ( ⁇ ) epimer A a -2 is formed as the major component.
- the the 7 ⁇ /7 ⁇ -epimer mixture of the ketone A-2 can then be converted further through a series of transformations, which may include hydrogenation, N- and/or O-demethylation, Grignard or lithium alkyl addition as shown in Scheme 3 below as described, for example, in Bentley, K.W., et al., Journal of American Chemical Society 89(13):3273-3280 (1967 ); Bentley, K. W., and Hardy, D. G., Journal of American Chemical Society 89(13):3281-3292 (1967 ); Marton, J., et al., Monatshefte für Chemie 125:1229-1239 (1994 ).
- a series of transformations which may include hydrogenation, N- and/or O-demethylation, Grignard or lithium alkyl addition as shown in Scheme 3 below as described, for example, in Bentley, K.W., et al., Journal of American Chemical Society 89(13):3273-3280 (1967 ); Bentley, K. W.,
- G is R 1 or a hydroxyl protecting group PG as defined above for Formula I
- R and R' are each independently alkyl, optionally substituted with 1, 2, or 3, substituents each independently selected from the group consisting of hydroxy, halo, haloalkyl, alkoxy, alkylcarbonyl, and alkoxycarbonyl, respectively, or are functional groups that can be converted to these groups.
- R" is as defined above for R 2 or a group that can be converted to R 2 .
- X is halogen or tosylate.
- HPLC METHOD 1 Column: Phenomenex Synergy Polar-RP, 50 ⁇ 3.0 mm, 2.5 ⁇ m Detection: UV 240 nm Injection Volume: 2.0 ⁇ L Flow Rate: 0.8 mL/min Column Temperature: Ambient Run Time: 15 min Mobile Phase A: 0.025% TFA in water Mobile Phase B: 0.025% TFA in acetonitrile Gradient Profile: Time Flow %A %B 1 0.00 0.8 90 10 2 5.00 0.8 89 11 3 12.00 0.8 45 55 4 12.01 0.8 90 10 5 15.00 0.8 90 10 HPLC METHOD 2 Column: Phenomenex Synergy Polar-RP, 50 ⁇ 3.0 mm, 2.5 ⁇ m Detection: UV 240 nm Injection Volume: 5.0 ⁇ L Flow Rate: 1.5 mL/min Column Temperature: Ambient Run Time: 25 min Mobile Phase A: 0.025% TFA in water Mobile Phase B: 0.025% TFA
- Tables 3 and 4 show that high recovery and high purity of the 7 ⁇ -epimer was achieved with 0.6 and 1.1 equivalents of acetic acid in alcohols. Recovery seemed to increase with decreasing polarity. High purity and a somewhat lower recovery of the 7 ⁇ -epimer was achived with 0.6 equivalents of fumaric acid. Fumaric acid and IPA afforded a somewhat lower purity in 1.1 eq. of acid.
- Compound 7 can be converted to its free base, compound 2, following the procedure described in Example 8 below.
- Method A To a mixture of 52 g of compound 7 , in ethyl acetate (1000 mL) and water (300 mL) was added 28% NH 4 OH and the pH of the mixture was adjusted to pH 9. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and filtered. The filtrate was concentrated to dryness. The crude product was triturated in methanol (MeOH) (400 mL) and stirred for 30 minutes under reflux.
- MeOH methanol
- Compound 4 can also be synthesized analogous to the procedure described in Example 14 using compound 2 instead of Compound 1.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Claims (18)
- Verfahren zum Erhöhen des Anteils von 7β-Epimer in einem 7α/7β-Epimer-Gemisch eines 7-substituierten 6α,14α-Ethenomorphinans oder eines 7-substituierten 6α,14α-Ethanomorphinans, wobei das Verfahren Folgendes umfasst:Inkontaktbringen einer Lösung des 7α/7β-Epimer-Gemischs mit einer Säure, um ein Präzipitat bereitzustellen, und Isolieren des Präzipitats, um ein isoliertes Präzipitat und eine Stammlösung bereitzustellen,wobei die Säure eine achirale Säure ist und wobei die Säure eine aliphatische Monocarbonsäure ist, die optional substituiert ist.
- Verfahren nach Anspruch 1,(A) wobei das 7-substituierte 6α,14α-Ethenomorphinan oder das 7-substituierte 6α,14α-Ethanomorphinan eine Verbindung der Formel II ist:G für R1 oder eine Hydroxylschutzgruppe PG steht;R1 für Wasserstoff, Alkyl, Alkenyl, Alkinyl, (Cycloalkyl)alkyl, (Heterocyclo)alkyl, Arylalkyl oder Heteroarylalkyl steht, wobei die Cycloalkyl-, Heterocyclo-, Aryl- und Heteroarylabschnitte davon optional mit 1, 2 oder 3 Substituenten substituiert sind, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Carboxy, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R2 für(a) Wasserstoff, Cyano, Alkylcarbonyl, Alkoxycarbonyl oder Carboxamido; oder(b) Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkenyl)alkyl, (Heterocyclo)alkyl, Arylalkyl, Heteroarylalkyl, (Arylalkoxy)carbonyl oder (Heteroarylalkoxy)carbonyl steht, wobei ein beliebiges davon optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R31 ausgewählt ist aus der Gruppe bestehend aus Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkyl)alkenyl, (Cycloalkenyl)alkyl, (Cycloalkenyl)alkenyl, (Heterocyclo)alkyl, (Heterocyclo)alkenyl, Arylalkyl, Arylalkenyl, Heteroarylalkyl, Heteroarylalkenyl, Alkylcarbonyl, (Arylalkyl)carbonyl und Formyl, wobei ein beliebiges davon, wenn es sich von Formyl unterscheidet, optional mit 1, 2, oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Hydroxyalkyl, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R4 ausgewählt ist aus der Gruppe bestehend aus Wasserstoff, Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkyl)alkenyl, (Cycloalkenyl)alkyl, (Cycloalkenyl)alkenyl, (Heterocyclo)alkyl, (Heterocyclo)alkenyl, Arylalkyl, Arylalkenyl, Heteroarylalkyl und Heteroarylalkenyl, wobei ein beliebiges davon, wenn es sich von Wasserstoff unterscheidet, optional mit 1, 2, oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl; und(B) wobei das 7-substituierte 6α,14α-Ethenomorphinan oder das 7-substituierte 6α,14α-Ethanomorphinan eine Verbindung der Formel III ist:G für R1 oder eine Hydroxylschutzgruppe PG steht;R1 für Wasserstoff, Alkyl, Alkenyl, Alkinyl, (Cycloalkyl)alkyl, (Heterocyclo)alkyl, Arylalkyl oder Heteroarylalkyl steht, wobei die Cycloalkyl-, Heterocyclo-, Aryl- und Heteroarylabschnitte davon optional mit 1, 2 oder 3 Substituenten substituiert sind, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Carboxy, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R2 für(a) Wasserstoff, Cyano, Alkylcarbonyl, Alkoxycarbonyl oder Carboxamido; oder(b) Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkenyl)alkyl, (Heterocyclo)alkyl, Arylalkyl, Heteroarylalkyl, (Arylalkoxy)carbonyl oder (Heteroarylalkoxy)carbonyl steht, wobei ein beliebiges davon optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R4 ausgewählt ist aus der Gruppe bestehend aus Wasserstoff, Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkyl)alkenyl, (Cycloalkenyl)alkyl, (Cycloalkenyl)alkenyl, (Heterocyclo)alkyl, (Heterocyclo)alkenyl, Arylalkyl, Arylalkenyl, Heteroarylalkyl und Heteroarylalkenyl, wobei ein beliebiges davon, wenn es sich von Wasserstoff unterscheidet, optional mit 1, 2, oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl; und
- Verfahren nach Anspruch 1 oder Anspruch 2, wobei das Präzipitat durch Filtration isoliert wird.
- Verfahren nach einem der Ansprüche 1-3,(A) wobei das Präzipitat einen erhöhten Anteil von 7β-Epimer als ein Salz relativ zu dem 7α/7β-Epimer-Gemisch enthält, oder(B) wenn in Bezug auf Anspruch 2, Option (B), wobei die Stammlösung einen erhöhten Anteil von entweder dem 7β-Epimer oder dem 7α-Epimer als ein Salz relativ zu dem 7α/7β-Epimer-Gemisch enthält, oder(C) wenn in Bezug auf Anspruch 2, Option (B), wobei das Präzipitat einen erhöhten Anteil von entweder dem 7β-Epimer oder dem 7α-Epimer als ein Salz relativ zu dem 7α/7β-Epimer-Gemisch enthält.
- Verfahren nach einem der Ansprüche 1-4, wobei die Säure von etwa 0,5 bis etwa 1,5 Äquivalenten auf der Grundlage der Menge des 7β-Epimers verwendet wird,
vorzugsweise wobei die Säure eine optional substituierte, gesättigte oder ungesättigte aliphatische Monocarbonsäure ist, weiter bevorzugt wobei die Säure eine gesättigte oder ungesättigte aliphatische C1-6-Monocarbonsäure ist, die optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Halogen und Hydroxy,
noch weiter bevorzugt wobei die Säure eine gesättigte, unsubstituierte aliphatische C1-4-Monocarbonsäure oder eine gesättigte aliphatische C1-4-Monocarbonsäure ist, die mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Fluor, Chlor, Brom, Iod und Hydroxy,
noch weiter bevorzugt wobei die Säure ausgewählt ist aus der Gruppe bestehend aus Essigsäure, Trifluoressigsäure, Trichloressigsäure und Tribromessigsäure. - Verfahren nach einem der Ansprüche 1-5, wobei die Lösung des 7α/7β-Epimer-Gemischs ein Lösungsmittel umfasst, vorzugsweise wobei das Lösungsmittel ein aliphatischer Alkohol, ein aromatisches Lösungsmittel oder ein aliphatischer Ether oder eine Kombination davon ist.
weiter bevorzugt wobei das Lösungsmittel Methanol, Ethanol, n-Propanol, iso-Propanol, Toluol, Cyclopentylmethylether oder eine Kombination davon ist. - Verfahren nach einem Ansprüche 1-6, wobei die Lösung bei einer Temperatur von etwa 50 °C bis etwa zum Siedepunkt der Lösung mit der achiralen Säure in Kontakt gebracht wird, vorzugsweise wobei die Temperatur von etwa 55 °C bis etwa zur Rückflusstemperatur des Lösungsmittels beträgt,
weiter bevorzugt wobei die Temperatur von etwa 60 °C bis etwa zur Rückflusstemperatur des Lösungsmittels beträgt. - Verfahren nach einem der Ansprüche 2-7, wobei G für R1 steht und R1 für Wasserstoff steht, oder
wobei G für PG steht und PG ausgewählt ist aus der Gruppe bestehend aus Alkyl, Arylalkyl, Heterocyclo, (Heterocyclo)alkyl, Acyl, Silyl und Carbonat, wobei ein beliebiges davon optional substituiert ist,
vorzugsweise wobei PG ausgewählt ist aus der Gruppe bestehend aus Alkyl, Arylalkyl, Heterocyclo, (Heterocyclo)alkyl, Benzoyl, (Benzyloxy)carbonyl, Alkoxycarbonyl, Alkylcarbonyl und Silyl, wobei ein beliebiges davon optional substituiert ist,
weiter bevorzugt wobei PG ausgewählt ist aus der Gruppe bestehend aus Methyl, tert-Butyl, optional substituiertem Benzyl, optional substituiertem Benzoyl, Acetyl, Trimethylsilyl, tert-Butyldimethylsilyl, tert-Butyldiphenylsilyl und tri-Isopropylsilyl. - Verfahren nach einem der Ansprüche 2-8, wobei R2 für Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkenyl)alkyl, (Heterocyclo)alkyl, Arylalkyl, Heteroarylalkyl, (Arylalkoxy)carbonyl oder (Heteroarylalkoxy)carbonyl steht, wobei ein beliebiges davon optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl,
vorzugsweise wobei R2 für C3-7 (Cycloalkyl) (C1-4)alkyl oder C3-7(Cycloalkenyl) (C1-4) alkyl steht, optional substituiert mit 1, 2 oder 3 Substituenten, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, C1-4-Alkyl, Halo, Halo (C1-4) alkyl, C1-4-Alkoxy, C1-4-Alkylcarbonyl und C1-4-Alkoxycarbonyl,
weiter bevorzugt wobei R2 für Cyclopropyl(C1-4) alkyl, Cyclobutyl (C1-4)alkyl, Cyclopentyl (C1-4)alkyl oder Cyclohexyl (C1-4)alkyl steht, optional substituiert mit 1, 2 oder 3 Substituenten, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, C1-4-alkyl, Halo, Halo (C1-4) alkyl, C1-4-Alkoxy, C1-4-Alkylcarbonyl und C1-4-Alkoxycarbonyl, oder
wobei R2 für unsubstituiertes C2-6-Alklenyl oder unsubstituiertes Cyclopropyl (C1-4) alkyl steht, vorzugsweise wobei R2 für Cyclopropylmethyl steht. - Verfahren nach einem der Ansprüche 2-9, wobei in Verbindungen der Formel II R31 ausgewählt ist aus der Gruppe bestehend aus C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-7-Cycloalkyl, C3-7-Cycloalkenyl, 5- bis 6-gliedrigem Heterocyclo, C6-12-Aryl, 5- bis 10-gliedrigem Heteroaryl, (C3-7-Cycloalkyl) (C1-6)alkyl, (C3-7-Cycloalkyl) (C2-6) alkenyl, (C3-7-Cycloalkenyl) (C1-6) alkyl, (C3-7-cycloalkenyl) (C2-6) alkenyl, (5- bis 6-gliedrigem Heterocyclo) (C1-6) alkyl, (5- bis 6-gliedrigem Heterocyclo) (C2-6) alkenyl, C6-12-Aryl (C1-6) alkyl, C6-12-Aryl (C2-6) alkenyl, 5- bis 10-gliedrigem Heteroaryl (C1-6) alkyl, 5- bis 10 gliedrigem Heteroaryl (C2-6) alkenyl, C1-6-Alkylcarbonyl, (C6-12-Aryl (C1-6) alkyl) carbonyl und Formyl, wobei ein beliebige davon, wenn es sich von Formyl unterscheidet, optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, C1-6-alkyl, Hydroxy (C1-4) alkyl, Halo, Halo (C1-4) alkyl, C1-6-Alkoxy, C1-6-Alkylcarbonyl und C1-6-Alkoxycarbonyl,
vorzugsweise wobei R31 für C1-6-Alkylcarbonyl steht, das unsubstituiert ist oder mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Halo, Halo (C1-4) alkyl, C1-6-Alkoxy, C1-6-Alkylcarbonyl und C1-6-Alkoxycarbonyl. - Verfahren nach einem der Ansprüche 2-10, wobei R4 ausgewählt ist aus der Gruppe von Wasserstoff, C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-7-Cycloalkyl, C3-7-Cycloalkenyl, 5- bis 6-gliedrigem Heterocyclo, C6-12-Aryl, 5- bis 10-gliedrigem Heteroaryl, (C3-7-Cycloalkyl) (C1-6) alkyl, (C3-7-Cycloalkyl) (C2-6) alkenyl, (C3-7-Cycloalkenyl) (C1-6) alkyl, (C3-7-Cycloalkenyl) (C2-6) alkenyl, (5- bis 10-gliedrigem Heterocyclo) (C1-6) alkyl, (5- bis 6-gliedrigem Heterocyclo) (C2-6) alkenyl, C6-12-Aryl (C1-6) alkyl, C6-12-Aryl (C2-6) alkenyl, 5- bis 10-gliedrigem Heteroaryl (C1-6) alkyl und 5- bis 10 gliedrigem Heteroaryl(C2-6)alkenyl, wobei es beliebiges davon, wenn es sich von Wasserstoff unterscheidet, optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, C1-4-alkyl, Halo, Halo (C1-4) alkyl, C1-6-Alkoxy, C1-6-Alkylcarbonyl und C1-6-Alkoxycarbonyl,
vorzugsweise wobei R4 für Wasserstoff oder unsubstituiertes C1-6-Alkyl steht. - Verfahren nach einem der Ansprüche 1-11, wobei das 7β-Epimer die Formel IV:
vorzugsweise wobei
R1 für Wasserstoff, C1-6-Alkyl oder Benzyl steht;
R2 für C2-6-Alkenyl, Cyclopropyl (C1-4) alkyl, Cyclopentyl (C1-4) alkyl oder Cyclohexyl(C1-4)alkyl steht, optional substituiert mit 1, 2 oder 3 Substituenten, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Halo, Halo (C1-4) alkyl, C1-4-Alkylcarbonyl und C1-4-Alkoxycarbonyl; und
R4 für Wasserstoff oder C1-6-Alkyl steht. - Verfahren nach einem der Ansprüche 1-12,(A) wobei der Anteil des 7β-Epimers in dem 7α/7β-Epimer-Gemisch mindestens etwa 20 % beträgt,
vorzugsweise wobei der Anteil des 7β-Epimers in dem 7α/7β-Epimer-Gemisch mindestens etwa 50 % beträgt, und/oder(B.1) wobei, wenn kein Bezug auf Anspruch 4, Option (B) vorliegt, der Anteil des 7β-Epimers in dem Präzipitat mindestens etwa 60 %, mindestens etwa 70 %, mindestes etwa 80 % oder mindestens etwa 90 % beträgt, oder(B.2) wobei, wenn in Bezug auf Anspruch 4, Option (B), der Anteil des 7β-Epimers in der Stammlösung mindestens etwa 60 %, mindestens etwa 70 %, mindestes etwa 80 % oder mindestens etwa 90 % beträgt. - Verfahren nach Anspruch 1 zum Herstellen einer 7β-substituierten Verbindung der Formel Vb:G für R1 oder eine Hydroxylschutzgruppe PG steht;R1 für Wasserstoff, Alkyl, Alkenyl, Alkinyl, (Cycloalkyl)alkyl, (Heterocyclo)alkyl, Arylalkyl oder Heteroarylalkyl steht, wobei die Cycloalkyl-, Heterocyclo-, Aryl- und Heteroarylabschnitte davon optional mit 1, 2 oder 3 Substituenten substituiert sind, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Carboxy, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R2 für(a) Wasserstoff, Cyano, Alkylcarbonyl, Alkoxycarbonyl oder Carboxamido; oder(b) Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkenyl)alkyl, (Heterocyclo)alkyl, Arylalkyl, Heteroarylalkyl, (Arylalkoxy)carbonyl oder (Heteroarylalkoxy)carbonyl steht, wobei ein beliebiges davon optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Alkyl, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R4 ausgewählt ist aus der Gruppe bestehend aus Wasserstoff, Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Heterocyclo, Aryl, Heteroaryl, (Cycloalkyl)alkyl, (Cycloalkyl)alkenyl, (Cycloalkenyl)alkyl, (Cycloalkenyl)alkenyl, (Heterocyclo)alkyl, (Heterocyclo)alkenyl, Arylalkyl, Arylalkenyl, Heteroarylalkyl und Heteroarylalkenyl, wobei ein beliebiges davon, wenn es sich von Wasserstoff unterscheidet, optional mit 1, 2, oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Halo, Haloalkyl, Alkoxy, Alkylcarbonyl und Alkoxycarbonyl;R5 für C1-6-Alkyl steht, das unsubstituiert ist oder mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Hydroxy, Hydroxy (C1-4) alkyl, Halo, Halo (C1-4) alkyl, C1-4-Alkylcarbonyl und C1-4-Alkoxycarbonyl;wobei das Verfahren Folgendes umfasst:wobei G und R2 so sind, wie vorstehend definiert, und einer Verbindung der Formel VII:
Durchführen einer Diels-Alder-Reaktion zwischen einer Verbindung der Formel VI:
optional Reduzieren der ersten Stammlösung und Inkontaktbringen der ersten Stammlösung mit einer Säure, um ein zweites Präzipitat bereitzustellen;
Isolieren des zweiten Präzipitats, um die Verbindung der Formel Vb als ein Salz und eine zweite Stammlösung zu erhalten; und optional Umwandeln des Säuresalzes in seine freie Base. - Verfahren nach Anspruch 14, wobei die erste Stammlösung vor Inkontaktbringen mit der Säure teilweise konzentriert wird, vorzugsweise wobei die teilweise konzentrierte Stammlösung erwärmt wird und optional ein Lösungsmittel zu der Stammlösung hinzugegeben wird, um ein beliebiges Präzipitat zu lösen, das sich während der Konzentration ausgebildet hat, um eine Lösung zu erhalten, weiter bevorzugt(A) wobei das Lösungsmittel ein aliphatischer Alkohol, ein aromatisches Lösungsmittel oder ein aliphatischer Ether oder eine Kombination davon ist,
vorzugsweise wobei das Lösungsmittel Methanol, Ethanol, n-Propanol, iso-Propanol, Toluol, Cyclopentylmethylether oder eine Kombination davon ist,
weiter bevorzugt wobei das Lösungsmittel iso-Propanol ist, und/oder(B) wobei die Lösung bei einer Temperatur von etwa 50 °C bis etwa zum Siedepunkt der Lösung mit der Säure in Kontakt gebracht wird,
vorzugsweise wobei die Temperatur von etwa 55 °C bis etwa zur Rückflusstemperatur beträgt,
weiter bevorzugt wobei die Temperatur von etwa 60 °C bis etwa zur Rückflusstemperatur beträgt. - Verfahren nach einem der Ansprüche 14-15, wobei die Säure von etwa 0,5 bis etwa 1,5 Äquivalenten auf der Grundlage der Menge des 7β-Epimers verwendet wird, und vorzugsweise
wobei die Säure eine optional substituierte, gesättigte oder ungesättigte aliphatische Monocarbonsäure ist,
weiter bevorzugt wobei die Säure eine gesättigte oder ungesättigte aliphatische C1-6-Monocarbonsäure ist, die optional mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Halogen und Hydroxy,
noch weiter bevorzugt wobei die Säure eine gesättigte, unsubstituierte aliphatische C1-4-Monocarbonsäure oder eine gesättigte aliphatische C1-4-Monocarbonsäure ist, die mit 1, 2 oder 3 Substituenten substituiert ist, wobei jeder unabhängig ausgewählt ist aus der Gruppe bestehend aus Fluor, Chlor, Brom, Iod und Hydroxy,
noch weiter bevorzugt wobei die Säure ausgewählt ist aus der Gruppe bestehend aus Essigsäure, Trifluoressigsäure, Trichloressigsäure und Tribromessigsäure. - Verfahren nach einem der Ansprüche 14-16, wobei der Anteil des 7β-Epimers in dem zweiten Präzipitat mindestens etwa 60 %, mindestens etwa 70 %, mindestens etwa 80 % oder mindestens etwa 90 % beträgt.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261747741P | 2012-12-31 | 2012-12-31 | |
US201361789269P | 2013-03-15 | 2013-03-15 | |
PCT/IB2013/002877 WO2014102591A1 (en) | 2012-12-31 | 2013-12-23 | PROCESS FOR PREPARING 7β-SUBSTITUTED 6α,14α -ETHENOMORPHINANS AND 7β-SUBSTITUTED 6α,14α-ETHANOMORPHINANS |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2941433A1 EP2941433A1 (de) | 2015-11-11 |
EP2941433B1 true EP2941433B1 (de) | 2019-08-07 |
Family
ID=50000019
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP13823994.2A Active EP2941433B1 (de) | 2012-12-31 | 2013-12-23 | Verfahren zur herstellung von 7-substituierten 6,14-ethenomorphinanen und 7-substituierten 6,14-ethenomorphinanen |
Country Status (9)
Country | Link |
---|---|
US (1) | US9834562B2 (de) |
EP (1) | EP2941433B1 (de) |
JP (2) | JP6181770B2 (de) |
AU (1) | AU2013369037C1 (de) |
CA (1) | CA2896919C (de) |
ES (1) | ES2748803T3 (de) |
IL (1) | IL239654B (de) |
MX (1) | MX2015008624A (de) |
WO (1) | WO2014102591A1 (de) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG11201707350TA (en) * | 2015-03-10 | 2017-10-30 | Rhodes Tech | Acetate salt of buprenorphine and methods for preparing buprenorphine |
JP2021104932A (ja) * | 2018-03-30 | 2021-07-26 | 日本ケミファ株式会社 | モルヒナン誘導体の製造方法 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB937214A (en) | 1961-06-02 | 1963-09-18 | J F Macfarlan & Company Ltd | Oripavine derivatives |
GB902659A (en) | 1961-02-02 | 1962-08-09 | J F Macfarlan & Company Ltd | A process for the production of a derivative of thebaine |
US3562279A (en) * | 1969-05-15 | 1971-02-09 | American Cyanamid Co | Substituted 7,8-dihydro - 6 - methoxy-6,14-endo(etheno or ethano)morphide - 7-ketones and n-cycloalkylmethyl - 7,8-dihydro - 6 - methoxy-6,14-endo(etheno or ethano) norcodide-7-ketones |
US3634430A (en) | 1969-06-13 | 1972-01-11 | American Cyanamid Co | Substituted 7-heterocyclic - 7 8-dihydro-6-(hydroxy or methoxy)-6 14-endo(etheno or ethano)codides and morphides |
WO1994006426A1 (en) | 1992-09-21 | 1994-03-31 | Qin Bo Yi | Methods for identifying and using low/non-addictive opioid analgesics |
KR100204659B1 (ko) | 1996-05-28 | 1999-06-15 | 강재헌 | 신규한 부프레노핀계 진통제용 화합물 |
US6067749A (en) | 1996-07-11 | 2000-05-30 | Tasmanian Alkaloids Pty. Ltd. | Papaver somniferum strain with high concentration of thebaine and oripavine |
US5869669A (en) | 1996-07-26 | 1999-02-09 | Penick Corporation | Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates |
EP0915094B1 (de) | 1997-03-27 | 2007-11-07 | Toray Industries, Inc. | Morphinanderivate und ihre medizinische Anwendung |
US6359139B1 (en) | 2000-11-07 | 2002-03-19 | Celgene Corporation | Methods for production of piperidyl acetamide stereoisomers |
GB0421687D0 (en) | 2004-09-30 | 2004-11-03 | Johnson Matthey Plc | Preparation of opiate analgesics |
AU2006215823A1 (en) | 2005-02-16 | 2006-08-24 | Micromet Ag | Use of activated polymers for separation of protein and polypeptide multimers |
CZ300995B6 (cs) * | 2005-12-20 | 2009-10-07 | Zentiva, A. S. | Zpusob výroby (2S,7´R)-2-[17´-(cyklopropylmethyl)-3´-hydroxy-4´,5´-epoxy-6´-methoxy-6´,14´-endoethanomorfinan-7´-yl]-3,3-dimethylbutan-2-olu |
CA2674915C (en) | 2006-10-17 | 2015-06-30 | Penick Corporation | Process for preparing oxymorphone |
US20080125592A1 (en) | 2006-10-17 | 2008-05-29 | Penick Corporation | Process for preparing oxymorphone, naltrexone, and buprenorphine |
JP2011506601A (ja) | 2007-12-17 | 2011-03-03 | マリンクロッド・インコーポレイテッド | ブプレノルフィンおよびブプレノルフィンの誘導体を調製するためのプロセス |
ES2462756T3 (es) | 2008-09-30 | 2014-05-26 | Mallinckrodt Llc | Procedimientos de síntesis de alcaloides opiáceos con formación reducida de impurezas |
WO2010039210A1 (en) | 2008-09-30 | 2010-04-08 | Mallinckrodt Inc. | Processes for the hydrogenation of opiate alkaloid derivatives |
US8232397B2 (en) | 2008-09-30 | 2012-07-31 | Mallinckrodt Llc | Processes for the production of buprenorphine with reduced impurity formation |
TWI630208B (zh) | 2008-12-08 | 2018-07-21 | 歐陸斯迪公司 | 二氫羥戊甲嗎啡 |
CA2802294C (en) | 2010-06-11 | 2016-05-10 | Rhodes Technologies | Process for n-dealkylation of tertiary amines |
-
2013
- 2013-12-23 ES ES13823994T patent/ES2748803T3/es active Active
- 2013-12-23 MX MX2015008624A patent/MX2015008624A/es active IP Right Grant
- 2013-12-23 AU AU2013369037A patent/AU2013369037C1/en active Active
- 2013-12-23 EP EP13823994.2A patent/EP2941433B1/de active Active
- 2013-12-23 WO PCT/IB2013/002877 patent/WO2014102591A1/en active Application Filing
- 2013-12-23 CA CA2896919A patent/CA2896919C/en active Active
- 2013-12-23 US US14/655,912 patent/US9834562B2/en active Active
- 2013-12-23 JP JP2015550153A patent/JP6181770B2/ja active Active
-
2015
- 2015-06-25 IL IL239654A patent/IL239654B/en active IP Right Grant
-
2017
- 2017-05-08 JP JP2017092698A patent/JP2017193549A/ja not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
None * |
Also Published As
Publication number | Publication date |
---|---|
AU2013369037C1 (en) | 2017-06-08 |
JP2016504346A (ja) | 2016-02-12 |
AU2013369037A1 (en) | 2015-07-23 |
US20160068538A1 (en) | 2016-03-10 |
AU2013369037B2 (en) | 2016-11-24 |
CA2896919A1 (en) | 2014-07-03 |
IL239654A0 (en) | 2015-08-31 |
US9834562B2 (en) | 2017-12-05 |
EP2941433A1 (de) | 2015-11-11 |
JP2017193549A (ja) | 2017-10-26 |
MX2015008624A (es) | 2016-12-08 |
CA2896919C (en) | 2019-01-29 |
ES2748803T3 (es) | 2020-03-18 |
IL239654B (en) | 2018-11-29 |
WO2014102591A1 (en) | 2014-07-03 |
JP6181770B2 (ja) | 2017-08-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2019229334B2 (en) | Substituted heterocycle fused gamma-carbolines synthesis | |
EP2888267B1 (de) | 1,3-dioxanmorphide und 1,3-dioxancodide | |
EP1144413B1 (de) | 2,5-diazabicyclo(2.2.1)heptanderivate, deren herstellung und deren verwendung in heilkunde | |
EP2758388B1 (de) | Neue bicyclische dihydrochinolin-2-on-derivate | |
EP2931724B1 (de) | Pyridonmorphinananaloga und biologische wirkung auf opioidrezeptoren | |
EP2941430B1 (de) | 7,8-cyclicmorphinan-analoge | |
EP2931726B1 (de) | Spirocyclische morphinane und deren verwendung | |
CN111344290B (zh) | 作为Wee1抑制剂的大环类化合物及其应用 | |
EP1161434B1 (de) | Pyridopyranoazepinderivate, ihre herstellung und therapeutische verwendung | |
TW200302725A (en) | N-substituted spiropiperidine compounds as ligands for ORL-1 receptor | |
EP3087057A1 (de) | Ringkontrahierte morphinane und verwendung davon | |
WO2005103039A1 (en) | 2- (3-aminopyrrolidin-1-yl) pyridines as melanin-concentrating hormone receptor an tagonists | |
EP0614898B1 (de) | Indol-derivat, verfahren zu dessen herstellung und dessen medizinische anwendung | |
EP2838883B1 (de) | Neue phenyltetrahydroisochinolin-derivate | |
EP2941433B1 (de) | Verfahren zur herstellung von 7-substituierten 6,14-ethenomorphinanen und 7-substituierten 6,14-ethenomorphinanen | |
CN117069720A (zh) | 一种5-ht2a受体激动剂及其制备方法和应用 | |
JP2001233876A (ja) | 三環式縮合異項環化合物、その製造法およびその医薬 | |
CN113717161B (zh) | 含氮饱和杂环化合物及其制备方法、药物组合物和应用 | |
Roth et al. | Functional Activity of Enantiomeric Oximes and Diastereomeric Amines and Cyano Substituents at C9 in 3-Hydroxy-N-phenethyl-5-phenylmorphans | |
EP3057940A1 (de) | Phenyldihydropyridinderivate als inhibitoren der aldosteronsynthase |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20150729 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
17Q | First examination report despatched |
Effective date: 20160520 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20190218 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP Ref country code: AT Ref legal event code: REF Ref document number: 1163675 Country of ref document: AT Kind code of ref document: T Effective date: 20190815 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602013058909 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: BOVARD AG PATENT- UND MARKENANWAELTE, CH |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: FP |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20191107 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20191107 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20191209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20191207 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20191108 Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2748803 Country of ref document: ES Kind code of ref document: T3 Effective date: 20200318 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20200224 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602013058909 Country of ref document: DE |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG2D | Information on lapse in contracting state deleted |
Ref country code: IS |
|
26N | No opposition filed |
Effective date: 20200603 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20191223 Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20191223 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: UEP Ref document number: 1163675 Country of ref document: AT Kind code of ref document: T Effective date: 20190807 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20131223 Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20190807 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20221122 Year of fee payment: 10 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230504 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20231121 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20231121 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20231122 Year of fee payment: 11 Ref country code: DE Payment date: 20231121 Year of fee payment: 11 Ref country code: AT Payment date: 20231123 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20231121 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20240102 Year of fee payment: 11 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20240102 Year of fee payment: 11 |